Treatments for stroke-induced cerebral ischemia (CI) have failed in part due to lack of efficacy against post- stroke neuroinflammation. However, while acute inflammation may contribute to worse patient outcomes, w e h y p o t h e s i z e t h a t chronic/delayed inflammation could promote brain repair, and may b e an attractive therapeutic target. In particular, we have demonstrated a significant role for the inflammatory cytokine interleukin-1 (IL-1) in CI. Although the deleterious role of IL-1 (the main isoform of IL-1 released following CI) in CI is established, IL-1 is also critically important and, in contrast toIL-1, may play a beneficial role. We have recently shown that IL-1 causes c u l t u r e d cells of the neurovascular unit to generate laminin globular domain 3 (LG3), the neuroprotective and pro-angiogenic protein fragment of the extracellular matrix component perlecan. Importantly, LG3 is persistently (weeks) generated in the brain after stroke, but whether this is caused, even in part, by IL-1, or is of any pathophysiologic or therapeutic benefit, is completely unknown. Our preliminary data now suggest that IL-1 activates brain endothelium, is pro-angiogenic in vitro, remains chronically elevated in stroked brains where it could persistently impact recovery, and when absent (IL-1 knockout mice (KO)) results in or contributes to diminished post-stroke angiogenesis. Therefore, we hypothesize that IL-1 is a key enhancer of angiogenesis (a brain repair mechanism) after stroke-induced CI via generation of LG3. To explore this hypothesis, we propose the following specific aims: 1) Determine the role of IL-1 in modulating angiogenesis in brain endothelium under normal conditions and after CI, 2) Determine the role of perlecan LG3 in IL-1 regulation of angiogenesis under normal conditions and after CI. We will use a number of in vitro angiogenesis assays and a transient middle cerebral artery occlusion model in wild-type and IL-1 KO mice to determine the angiogenic effects of IL-1 in vitro and in vivo. Functional/behavioral analysis will also be performed to correlate the extent of angiogenesis and infarct volume with functional recovery. The importance of LG3 to IL-1 angiogenesis effects in vitro and in vivo (after stroke) will be determined using a perlecan transgenic mouse that expresses 10% of normal total perlecan levels (pln -/-). Finally, we will employ various genetic and biochemical methods to determine how IL-1 increases LG3 generation in brain endothelial cells in vitro with a focus on key cellular proteases, and determine whether disruption of this impacts IL-1 angiomodulatory activity. Successful completion of this proposal will demonstrate a novel beneficial effect of inflammatory cytokines, specifically IL-1, in brain recovery after stroke.